Chloramphenicol (CAP, RNHCOCHCl2) is dehalogenated to CAP aldehyde (RNHCOCHO) in rat cytosol predominantly by glutathione transferase A. This reaction likely involves the initial displacement of a chlorine by glutathione (GSH) to produce an alpha halothioether intermediate (RNHCOCHCl-SG). This product is expected to react rapidly with water to yield CAP aldehyde (RNHCOCHO) and GSH. Thiamphenicol, TAP, the p-methylsulfonyl derivative of CAP, is dechlorinated to an aldehyde by this enzyme system to a significantly slower extent than is CAP. In contrast, neither enflurane (CF2OCF2CHClF) NOR halothane (CF3CHBrCl) is dehalogenated to aldehydes by this enzyme system. This finding suggests that the GSH dependent dehalogenases are not involved in the liver and kidney toxicity produced by these compounds.